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Abstract

Objective To provide an overview of drug use in children in three
European countries.

Design Retrospective cohort study, 2000-5.

Setting Primary care research databases in the Netherlands (IPCI),
United Kingdom (IMS-DA), and Italy (Pedianet).

Participants 675 868 children aged up to 14 (Italy) or 18 (UK and
Netherlands).

Main outcome measure Prevalence of use per year calculated by drug
class (anatomical and therapeutic). Prevalence of “recurrent/chronic” use (three
or more prescriptions a year) and “non-recurrent” or “acute” use (less than
three prescriptions a year) within each therapeutic class. Descriptions of the
top five most commonly used drugs evaluated for off label status within each
anatomical class.

Results Three levels of drug use could be distinguished in the study
population: high (>10/100 children per year), moderate (1-10/100 children
per year), and low (<1/100 children per year). For all age categories,
anti-infective, dermatological, and respiratory drugs were in the high use
group, whereas cardiovascular and antineoplastic drugs were always in the low
use group. Emollients, topical steroids, and asthma drugs had the highest
prevalence of recurrent use, but relative use of low prevalence drugs was more
often recurrent than acute. In the top five highest prevalence drugs topical
inhaled and systemic steroids, oral contraceptives, and topical or systemic
antifungal drugs were most commonly used off label.

Conclusion This overview of outpatient paediatric prescription
patterns in a large European population could provide information to prioritise
paediatric therapeutic research needs.

Introduction

Recent years have seen growing concerns about the incompleteness of the evidence
relating to the efficacy and safety of drugs used in children. Almost all of the
drugs prescribed to children are the same as those originally developed for adults.
They are often prescribed on an unlicensed or “off label” basis (percentages ranging
from 11-80%1) simply by extrapolating data
for adults, without conducting any paediatric clinical, kinetic, dose finding, or
formulation studies in children. Diseases in children, however, might be different
from their adult equivalents, and the processes underlying growth and development
might lead to a different effect or an adverse drug reaction unseen in adults
(Reye’s syndrome is an outstanding example).

To provide legitimate and appropriate treatment for children’s diseases, new
legislation was approved in the United States in 2003 and the European Union in
2007.2 Both the Food and Drug
Administration (FDA) and the European Medicines Agency for the Evaluation of
Medicinal Products (EMEA) now offer extensions of drug licences to companies who
provide evidence concerning the efficacy and safety in children of new drugs or off
label drugs.3456 The World Health Organization underlines
the need for these actions and in December 2007 launched a global campaign to “make
medicines child size” to address the need for improved availability and access to
safe child specific medicines for all children.7

We investigated the current use of paediatric drugs in children in three European
countries, using population based data on primary care prescriptions.

Methods

Setting

The primary care of children is entrusted to general practitioners in the UK and
the Netherlands and to paediatricians in Italy.89 Access to health care is free in Italy
and the UK and fully covered by healthcare insurance in the Netherlands. In
these countries, primary care physicians are responsible for children’s health
care, which means that all clinical information concerning the patients
(including summaries of specialist and hospital care) is kept in their medical
records. As all children need to be registered with a general practitioner in
the Netherlands and UK and with a family paediatrician in Italy, the databases
are population based.9

Data collection

We used the same protocol to study prescription patterns in the three countries,
making use of the Pedianet database (paediatric electronic medical records from
150 paediatricians since 2000) in Italy,10 the integrated primary care information (IPCI) database (comprising
adult and paediatric electronic medical records from more than 400 doctors since
1996) in the Netherlands,81112 and the IMS disease analyser
database (IMS-DA: electronic medical records on adults and children from 670
doctors) in the UK.13 All of these
databases include the complete automated medical records of primary care
physicians and have been used and proved valid for pharmacoepidemiological
research.9 The age and sex
distribution in the various databases is representative for the country of
origin.

Study population and drug prescriptions

The dynamic study population in each country consisted of all children aged 0-18
years (0-14 years in Italy) who had a database history of at least six months or
who were born during the study period (1 January 2000 to 31 December 2005). We
calculated the person time of follow-up for each child, stratified by calendar
year and age group. Age was assessed on 1 January of each year and grouped
according to the guidelines of the International Conference of Harmonization
(ICH) as <2, 2-11, and 12-18.14
We could not further stratify the youngest age category into newborns (<1
month) and infants (1-24 months) as exact dates of birth were not available
because of privacy regulations. Each child was followed from the start of the
study period or the date of registration with the primary practice (whichever
was the latest) until the cancellation of registration with the practice or the
end of the study period. We used the person time accumulated in each calendar
year as the denominator to calculate prevalence rates. Over the study period
children could contribute to more than one age category.

All prescribed drugs in children during follow-up were retrieved from the
prescription data in the database. The drug prescriptions were grouped on the
basis of the WHO Anatomical Therapeutic Chemical (ATC) classification system,
which made comparison between countries possible.

Statistical analysis

We estimated user prevalence rates (per 1000 person years) by counting the number
of children using a specific drug in a specific calendar year. The prevalence
rates were calculated by age and country to account for differences in
distributions between populations and to allow for direct comparisons within
groups. User prevalence rates should be interpreted as the number of children
per 1000 who use a specific class of drug in one year. We could not calculate
prevalence of drug use for children aged 15-18 in Italy because all of children
were censored at the age of 15. We used person years rather than individuals as
the denominator because of the dynamic nature of age and the population.

For each anatomical class of drug we assessed the age and country specific user
prevalence rates for all individual drugs in 2005. We evaluated the five drugs
with the highest prevalence per anatomical class in each country for off label
status considering age only. A drug was considered to be off label for age if
the child’s age at the time of use was below the lowest approved age mentioned
in the summary of product characteristics of that drug in each country.15 Within each therapeutic drug level, we
separately estimated the prevalence of children presenting “recurrent/chronic”
(three or more prescriptions a year) versus “non-recurrent” or “acute” drug use
(less than three prescriptions a year), and the ratio between them to identify
the treatments more commonly used for chronic than acute paediatric diseases. We
used χ2 test to compare user prevalence rates.

Results

Study population

Our population of 675 868 children generated 2 334 673 person years of follow-up
(table 1)​1);; the mean individual follow-up was
3.5 years. Most of the children (66%) came from the IMS database in the UK, 19%
from Italy, and 15% from the Netherlands. The databases recorded more than five
million paediatric prescriptions. In all three countries the prescription rate
was highest for the children aged under 2 and, in each age group, was
significantly higher in the UK and Italy than in the Netherlands
(P<0.001) (table 1).

Drug use by anatomical class

The highest prevalence rates among the children aged under 2 were for
anti-infective drugs, respiratory drugs, and dermatological drugs, which were
used by 48%, 30%, and 30% of the children, respectively (fig 1)​1).. The other common prescriptions were for
gastrointestinal drugs (user prevalence of 20%), drugs for the nervous system
(14%) and drugs for sensory organs (19%). Blood and blood forming organs,
hormonal, and musculoskeletal system drugs were used in 1-10% of the children,
and cardiovascular, genitourinary, antineoplastic, and antiparasitic drugs by
less than 1%.

Fig 1 One year prevalence of drug prescriptions by age
(<2, 2-11, 12-18 years), and anatomical class

Among the children aged 2-11, the prevalence of use of anti-infective,
respiratory, and dermatological drugs decreased to 30%, 21%, and 17%,
respectively. The prevalence was 1-10% for gastrointestinal, hormonal,
musculoskeletal system, nervous system, antiparasitic, and sensory organ drugs;
and less than 1% for blood and blood forming organs, cardiovascular,
genitourinary, and antineoplastic drugs.

In adolescents (12-18 years), anti-infective, respiratory, and dermatological
drugs were used by more than 10% per year. Most of the other drug classes were
used by 1-10%, but the prevalence of use of cardiovascular and antineoplastic
drugs was less than 1%.

Regarding sex differences, in the youngest age groups, most of the drugs were
equally prescribed to both sexes or more commonly prescribed to boys than girls
(rate ratio <1), particularly anti-infective and respiratory drugs. This
pattern reversed in adolescence, when user prevalence for almost all drug
classes (except non-sex hormones) was higher among girls than boys. This sex
pattern, which was consistent across countries, was most pronounced for
genitourinary drugs, with a user prevalence more than 60 times higher in girls
because they include oral contraceptives, which accounted for 95% of the use of
genitourinary drugs in girls. The use of drugs for blood and blood forming
organs (mainly iron preparations) was also markedly higher among adolescent
girls.

The age trend of prevalence of use was consistent across countries, although
there were some variations in the age specific rates (fig 2)​2).. In particular, the UK showed the highest prevalence of
alimentary drug use in children aged under 2, and the prevalence of
prescriptions of dermatological drugs was threefold to fourfold higher in the UK
and the Netherlands than in Italy (both P<0.001). The prevalence of
genitourinary drug use (almost all oral contraceptives) was high in adolescent
girls in the Netherlands (P<0.001). In Italy, the use of hormones (almost
all systemic corticosteroids) was 10-fold higher in children aged <2
(P<0.001) and fivefold higher in those aged 2-11 (P<0.001);
respiratory drug use was also greater in Italy than in the other two countries
(P<0.001). The prevalence of the use of anti-infective drugs and drugs
for musculoskeletal disorders was much lower in the Netherlands; the prevalence
of prescriptions for drugs for the nervous system (including paracetamol, which
can be prescribed in UK) was much higher in the UK; and the use of drugs for the
sensory organs was much less in Italy.

Fig 2 Year prevalence of drug use (per 1000 person years) by
age (<2, 2-11, 12-18), country, and anatomical class for most
prevalently used drug classes (data for Italy excluded age category
...

Prevalence of drug use in therapeutic class

Within the most commonly used anatomical drug classes, antibacterials accounted
for most of the anti-infective drug use; and the therapeutic classes
antiasthmatics, other respiratory products, and nasal preparations were the most
commonly used drugs in the respiratory group (table 2)​2).. The therapeutic classes with the highest prevalence of use
among the dermatological drugs were topical corticosteroids and emollients and
barrier creams. Many therapeutic classes in the group of alimentary drugs
(laxatives, antidiarrhoeal drugs, drugs for acid disorders) had a considerable
prevalence of use. The most commonly prescribed drugs in the other classes were
antianemia medications, cardiac drugs (mainly digoxin), sex hormones, oral
corticosteroids, non-steroidal anti-inflammatory drugs, analgesics, and
ophthalmological drugs.

Prevalence of acute use (<3 prescriptions per year) and recurrent
use (≥3 prescriptions per year) by age and therapeutic level (prevalence
per 1000 person years), ranked by the ratio...

Ranking of user prevalence rates specific for age over the entire range of drugs
showed that antibacterials are the most commonly prescribed drugs in all age
groups (table 3)​3) and are prescribed to at
least twice as many children as the second most commonly used drug in each age
category. The second most commonly used drug changed by age from
ophthalmological drugs (<2 years) to drugs for obstructive airway disease
(2-11) to sex hormones (12-18).

Top 10 most commonly used therapeutic classes in various age
categories

When we ranked the therapeutic classes within each anatomical class on the basis
of the ratio between recurrent (chronic) and non-recurrent (acute), we observed
a different pattern (table 2).​2). The drugs with
a ratio of >1 (indicating mostly chronic/recurrent use) were often those
with a low prevalence of use (except for sex hormones): antidiabetics,
digestives, bile and liver therapy, antithrombotic agents, agents acting on the
renin-angiotensin system, lipid lowering drugs, sex hormones, thyroid
therapeutic agents, immunosuppressive agents, muscle relaxants, antiepileptics,
and psychoanaleptics (table 2).​2). In absolute
terms, emollients, topical corticosteroids, sex hormones, anti-infectives, and
drugs for obstructive airway disease showed the highest prevalence of recurrent
use.

Most commonly used drugs in each anatomical class

In the most commonly used anatomical classes (dermatology, anti-infectives, and
respiratory system), the most common individual dermatological drugs were
fusidic acid (except for Italy), topical steroids, and topical
imidazole/triazole derivatives (tables 4, 5, and 6)​6)
​​.. The topical triazoles/imidazoles were off
label in most countries for at least one or more age categories. In the
anti-infectives group (J), penicillin derivatives (amoxicillin, co-amoxiclav,
and phenoxymethylpenicillin) followed by macrolides (erythromycin,
clarithromycin) were the most common, cefalexin (UK, <2 year) was the
only off label drug. Oral aciclovir was one of the top five anti-infective drugs
in Italy. Among the respiratory drugs, salbutamol and inhaled steroids
(beclometasone, fluticasone, flunisolide), antihistamines (cetirizine,
loratidine, clorpheniramine), and xylometazoline were most commonly prescribed.
Beclometasone, xylometazoline, and cetirizine were off label in the youngest
children (<2 years) in the UK and the Netherlands.

Most commonly used drugs (use per 1000 children per year) by anatomical
level and age in 2005 plus paediatric licensing status in Italy

In the moderately used drugs (gastrointestinal, genitourinary, nervous system,
and sensory system drugs), the most commonly prescribed alimentary tract drugs
(A) were laxatives (lactulose), miconazole, domperidone, and mebeverine. Only
ranitidine and laurilsulfate were off label in children <2 years. For the
genitourinary drugs, the top five in the Netherlands and UK were oral
contraceptives and topical antifungals (miconazole), whereas in Italy (up to age
12) oestrogens, drugs to treat incontinence, and antiseptics were the most
commonly prescribed. The percentage of off label use of oral contraceptives and
antifungals was high in the Netherlands and the UK. Among drugs for the nervous
system, paracetamol is clearly the most used (but probably underestimated
because of high over the counter use); methylphenidate (Netherlands and UK),
lidocaine (Netherlands), pizotifen (UK), fluoxetine (UK) diazepam, niaprazine
(Italy), and valproic acid (Italy) were also in the top five of at least one
country. None of them was used off label, except diazepam for children under 12
in the Netherlands. In the group of sensory organ drugs many different drugs
were used in the various countries, the most commonly prescribed drugs in the
Netherlands (fusidic acid, levocabastine) and the UK (chloramphenicol) were off
label.

The low prevalence drugs comprised many classes (groups blood, cardiovascular,
hormonal, antineoplastic, musculoskeletal, antiparastic). In the blood forming
organs group (B), phytomenadione, iron, tranexamic acid, platelet inhibitors,
and vitamin K antagonists were most commonly prescribed. Salicylic acid
derivatives were off label. In the cardiovascular drug group topical steroids
(antihaemorrhoid creams), topical anaesthetics (lidocaine, oxetacaine), β
blockers (propranolol, atenolol), furosemide, disopyramide, adrenaline
(epinephrine), and enalapril were most common. Furosemide, β blockers,
adrenaline, and topical (antihaemorrhoidal) steroids were off label in at least
one country. For the non-sex hormones, desmopressin, oral steroids
(dexamethasone, prednisolone and prednisone), levothyroxine and glucagons) were
the most commonly prescribed drugs. Only the oral steroids were off label
(Netherlands and UK only). The most commonly prescribed antineoplastic and
immunomodulating drugs differed substantially between countries but were almost
always off label. In the musculoskeletal drug group non-steroidal
anti-inflammatory drugs were the most commonly prescribed, with important
sequence differences between countries but little off label use except in Italy,
where the number one and two drugs (ibuprofen and morniflumate) were off label.
In all countries the number one antiprotozoal drug was mebendazole, with little
off label drug use.

Discussion

We have provided a unique overview of primary care prescription patterns in a large
multinational European paediatric population. The data could be used to improve the
prioritisation of research into long term safety of paediatric drugs, as well as
efficacy and effectiveness studies in paediatric medicine. Off label use in some of
the most commonly and recurrently used drugs is high (such as oral contraceptives)
and these should be considered for prioritisation.

Prioritisation of research on drug safety in paediatrics

We recommend two important assessments in prioritising research needs in
medicines for children: public health assessment,16 comprising the severity and prevalence of disease and
the availability of treatment alternatives; and assessment of use. This may
comprise the frequency or volume of use and the licensing/labelling status of
medicines for children. The use of off label and unlicensed medicines implies
that there are no proper labelling and dosing recommendations, which can
potentially be harmful to children.17181920 Therefore off label and unlicensed
medicines should be a higher priority for research than licensed/on label
medications, especially if no data on safety and efficacy in children are
available. We focused on assessing the volume and labelling status to provide
knowledge to experts and facilitate research prioritisation that includes both
the public health as well as the assessment of use.

Our data on use support the conclusions of the recently published EMEA
consensus/expert derived list of research priorities concerning off patent
medicinal products,16 which emphasised
the need for paediatric studies of the safety of topical, systemic, and inhaled
steroids. Steroids are associated with impaired growth,21 abnormalities in glucose metabolism,22 and adrenal suppression.2324 Of these, growth retardation is the
most common and is of particular concern in children. The extent of growth
suppression varies with the method of administration (such as inhaled or oral)
and the duration of treatment, as well as with the type and dose of
glucocorticoid used.2125 EMEA also lists topical and systemic
antifungals (imidazoles/triazoles), acid reducing drugs, and antineoplastic
drugs as research priorities. These drugs are often or recurrently used and are
mostly off label. Many other drugs listed did not appear as commonly used drugs
in our study and, on the basis of frequency of use in primary care alone, would
not be considered as priorities but apparently were considered priorities for
other reasons. On the other hand, sex hormones are not listed on the priority
list, whereas they are commonly and recurrently prescribed, mostly off label.
Few long term safety studies on the use of sex hormones in adolescents are
available and to our knowledge there are no randomised controlled trials on
their safety and efficacy in this age group. The use of oral contraceptives in
adolescents has been associated with an increased risk of lower bone mineral
density, higher serum cholesterol concentrations, triglyceridaemia,262728 cardiovascular events (such as
myocardial infarction and stroke), and venous thromboembolism.2930313233 As the use of sex hormones in young
adolescents is relatively high, leading to a long duration of use, further
studies on the efficacy and long term safety effects of these drugs in young
women are warranted.

Although patterns of drug use and labelling status can inform decisions on
prioritisation of research, these data inform also us about suboptimal use and
might even uncover undesirable prescribing practices. For example, fusidic acid
and chloramphenicol are often used and often off label (tables 4-6). In the
Netherlands, fusidic acid is prescribed for the treatment of conjunctivitis,
similar to chloramphenicol in the UK. The beneficial effect of antibiotics in
the treatment of this condition, however, has not been proved.3435 Indeed acute bacterial
conjunctivitis is often a self limiting condition, and topical antibiotic use
offers only marginal benefit in improving clinical outcomes; hence the emphasis
should be on educating clinicians not to prescribe such treatment rather than a
call for more research.3637 Another example underlining the need
for education rather than research is the cough and cold medications. These
drugs are not only available over the counter but are also often prescribed,
which should be strongly discouraged because of reports of death and lack of
efficacy.38

Patterns of drug use

We found that the prevalence of the most commonly prescribed drugs in primary
care is highest in children aged under 2, that the most commonly used drugs
(anti-infectives, dermatologicals, and respiratory drugs) are the same in all
three age categories, and that almost all other drugs are used by less than 10%
of children a year. In general, we can categorise three groups of drug use:
drugs used by more than 10% of children a year, those used by 1-10%, and those
used by less than 1%. The use of the high prevalence drug classes decreases with
age but remains high, whereas the use of the lowest prevalence drug groups
increases to a moderate prevalence rate in adolescence, except in the case of
cardiovascular and antineoplastic agents. Only a few therapeutic drug classes
accounted for most use in a specific anatomical class: antibacterials, topical
corticosteroids, antiasthma and antianaemia medications, cardiac drugs, sex
hormones, oral corticosteroids, non-steroidal anti-inflammatory drugs,
analgesics, and ophthalmological drugs. Relatively speaking, the high prevalence
drugs were more often used for acute use. Only 12 drug classes (antidiabetics,
digestives, bile and liver therapy, antithrombotic agents, drugs affecting the
renin-angiotensin system, lipid lowering drugs, sex hormones, thyroid
therapeutic agents, immunosuppressive agents, muscle relaxants, antiepileptics,
and psychoanaleptics) were prescribed more often for recurrent than acute use.

We observed an age related sex reversal: prevalence rates for drug use were
consistently higher in adolescents girls than in adolescent boys (except in the
case of non-sex hormones), whereas the opposite was true in the younger age
categories. This agrees with findings from previous Dutch and Danish
studies.3940

Interestingly, the percentage of off label use varied highly between countries,
and similar drugs differed in off label status between countries. This confirms
that the differences in the paediatric status of the drugs, instead of the
different prescription habits or medical cultures as postulated by many authors,
represent the real reason for the variability reported by years and from many
European studies and surveys on the off label use in children.41

Previous studies

Our study was population based, had a large sample size, and covered different
European countries. Previous European studies have been country or region
specific and have concentrated on specific conditions, except for studies from
Sweden, the Netherlands, and Denmark in the late 1990s and a recent Italian
study covering data from 2000-6.40424344 These studies took all types of
drugs into account but the methods to calculate prevalence and ranking (on the
basis of number of dispensed boxes or user prevalence) and age ranges varied
largely, which complicates direct comparisons. The overall results—highest drug
use in lowest age category, ranking of the most commonly used drugs
(anti-infectives, respiratory, and dermatological drugs), and sex pattern (more
prescriptions for girls than boys after the age of 10)—are consistent with our
findings.394045

Potential of multi-country database studies

We have shown the potential of studying the primary care prescribing of a wide
range of drugs using multiple databases. As all databases include outcome data,
such as morbidity and mortality, they can also be used for studies of paediatric
drug safety. The country specific estimates provide insights into prescription
differences and allow a search for high prevalence countries regarding drug
prescribing.

Limitations

We captured only outpatient, primary care drug prescriptions and not use of over
the counter drugs (which resulted in a substantial underestimation of the use of
paracetamol and phytomenadione, and potentially other drugs such as cough and
cold medications). In the Netherlands, the UK, and Italy, most health problems
are dealt with in primary care,8 and as
drug prescriptions by a specialist for a chronic disease are often continued by
general practitioners or paediatricians, most of them are picked up. Drugs given
in hospital and the monitoring of chemotherapeutic and biological drugs are
unlikely to be fully captured by our databases. Despite differences in the
absolute prevalence rates of drug prescribing and the types of drugs prescribed,
age and sex patterns were consistent in the three countries. As the UK accounted
for 60% of the study population, however, the pooled results are inevitably
dominated by UK prescription patterns so we conducted stratified analyses as
much as possible. Because of the nature of the databases, we studied drug
prescriptions rather than drug intake, and so the prevalence of actual drug
exposure might be lower than estimated here.

What is already known on this topic

Most previous research on drug use in children has focused on
specific high use areas such as antibiotics and respiratory and
neuropsychiatric drugs, therefore most of these drugs have a
paediatric licensing status

Paediatric expert groups have been established by the European
Medicines Evaluation Board (EMEA) to identify those drugs that
are important for the paediatric community and that require
additional efficacy and safety data

What this study adds

Data on frequency of prescriptions and off label status of drugs
could provide objective evidence for the prioritisation of
research in paediatric drugs

Information on the safety and efficacy of some of the most
commonly used drugs in children (such as oral contraceptives,
steroids, and triazoles/imidazoles) is lacking, and not all such
drugs are on the list of research needs

Notes

We thank Peter Stephens of IMS Health for providing the IMS-DA database and
all the physicians contributing data to the databases.

Contributors: All authors conceived the idea for the study, designed the
study, and analysed and interpreted the data. MCJMS and KMCV drafted the
manuscript, which was revised by AN and EFS. AC and ICKW supervised the
study. MCJMS is guarantor.

Funding: The study was funded by the European Community’s 6th Framework
Programme, project No LSHB-CT-2005-005216: TEDDY: Task force in Europe for
Drug Development for the Young. The funding agency had no role in the
collection of data, the analysis or interpretation of the data, or of the
decision to submit. ICKW’s post was funded by a UK Department of Health
Public Health Career Scientist Award.

Competing interests: MCJMS has received various unconditional research grants
from pharmaceutical companies (Merck, Pfizer, Johnson and Johnson, Amgen,
Roche, Altana, GSK) and is consultant to Pfizer, Celgene, Servier, and
Sanofi Aventis. AN has been reimbursed by Pfizer for attending several
conferences. GP has received unconditional research grants from Merck and
BMS). CG has received fees for speaking, consulting, and research from
Sanofi Pasteur, GSK, Abbott, BMS, Gilead, Abbott, Tibotec, Boheringer
Ingelheim, GSK-Biologicals). LC has received research grants from GSK,
Abbott, Merck, and BMS.

Ethical approval: The use of IMS data for this study has been reviewed by an
independent scientific and ethics committee.

Notes

References

2. Regulation (EC) No 1901/2006 of the European
Parliament and of the Council of 12 December 2006 on medicinal products for
paediatric use. Paediatric regulation. Official Journal of the European
Union 2006;18:L378/1.

17. European Medicines Agency. Evidence of harm
from off-label or unlicensed medicines in children. European Medicines
Agency pre-authorisation evaluation of medicines for human use
London: EMA, 2004. (EMEA/126327/2004.)